High-risk Leukemia: Blocking the Shuffle

Someday, children like Reagan Kuehn may not have to undergo transplants for Ph-positive ALL, thanks to research conducted at
St. Jude.

St. Jude scientists develop a new treatment strategy that offers hope to children and adults with a form of high-risk leukemia.

Like a deck of cards shuffled by a clumsy dealer, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) occurs when portions of two chromosomes swap places and begin a process that leads to the unchecked cell growth characteristic of cancer. This subtype of ALL is difficult to treat and causes more complications for patients than traditional ALL.

This was the case for Reagan Kuehn in October 2012. When the normally outgoing and lively toddler became sluggish and developed fevers, a visit to the pediatrician indicated that her liver and spleen were enlarged—a symptom of leukemia. Doctors referred her to St. Jude Children’s Research Hospital, where Reagan began a two-year treatment plan for Ph-positive ALL.

But clinicians quickly realized that Reagan’s leukemic cells were resistant to chemotherapy. the little girl received a bone marrow transplant and is now back to being the rambunctious child she was before her disease was diagnosed.

Brian Koss (foreground) and Joseph Opferman, PhD, of St. Jude Biochemistry, discuss research findings that hold promise for patients with a rare form of high-risk leukemia.

Although transplants are often an effective treatment for Ph-positive ALL, a new therapy developed in the lab of Joseph Opferman, PhD, of St. JudeBiochemistry, might be even more effective in killing leukemia cells, possibly eliminating the need for transplants.

In the lab

The swapping or translocation of pieces of the ABL1 and BCR genes—found respectively on the ninth and 22nd chromosomes—leads to production of a protein called BCR-ABL, which plays a key role in the development of Ph-positive ALL.

This environment paves the way for proteins to wreak havoc by blocking the process of programmed cell death known as apoptosis, which is how the body eliminates damaged, dangerous or unneeded cells. St. Jude researchers identified one of those proteins, MCL1, and discovered that it is essential for preventing leukemia apoptosis.

What is Ph-positive ALL?

Philadelphia chromosome-positive acute lymphoblastic leukemia (also known as Ph-positive ALL) is a high-risk cancer that accounts for about 40 percent of ALL in adults and about 5 percent in children. Ph-positive ALL is a subtype of acute lymphoblastic leukemia. It received its name because it was discovered in 1960 by a team of scientists working in Philadelphia. The Philadelphia chromosome occurs when portions of chromosomes 9 and 22 translocate or change places.

The chromosomal rearrangement brings together pieces of the BCR and ABL1 genes. The ABL1 gene from chromosome 9 fuses to a portion of the BCR gene on chromosome 22 to create an elongated chromosome 9 and a smaller chromosome 22—the Philadelphia chromosome. This fusion leads to production of the BCR-ABL protein, which fuels the unchecked cell growth that is a hallmark of cancer.

Using these findings, the scientists began combining drug therapies to find ways to reduce MCL1 levels and offer hope to children and adults with the disease.

The investigators combined drugs that reduce MCL1’s levels in leukemia cells with a drug that targets a different protein that inhibits cell death. The result was an increase in apoptosis in leukemia cells.

“These findings suggest that disrupting the ability of leukemia cells to produce MCL1 renders those cells vulnerable to other drugs,” Opferman says. “That’s exciting because we already have drugs like imatinib and other inhibitors that reduce MCL1 production in tumor cells, leaving those cells vulnerable to being pushed into death via apoptosis by other drugs already in development.”

Beyond leukemia

The research could also enhance the effectiveness of drugs used to treat other cancers in which MCL1 levels are elevated.

Opferman’s study found that MCL1 was required for leukemia cells to survive throughout the Ph-positive ALL disease process. Scientists also showed that deleting MCL1 from leukemia cells blocks cancer’s progression.

“Together these findings suggest that MCL1 is a relevant target for cancer treatment,” said Brian Koss, a staff scientist in Opferman’s laboratory, “but efforts should focus on diminishing the expression of MCL1, rather than completely eliminating its function.”